Synergistic cytotoxicity effect of histone deacetylase inhibitor combined with paclitaxel on lung cancer cell lines and its mechanism
10.3321/j.issn:1000-467X.2009.12.008
- VernacularTitle:组蛋白去乙酰化酶抑制剂协同紫杉醇对人肺癌细胞株抑制作用及机制
- Author:
Zhang DONG
1
;
Liu CHANG-TING
;
Yu XIAO-DAN
;
Liu YAN
Author Information
1. 解放军总医院
- Keywords:
lung cancer;
histone deacetylase;
trichostatin A;
paclitaxel;
apoptosis;
ERK
- From:Chinese Journal of Cancer
2009;28(12):1270-1276
- CountryChina
- Language:Chinese
-
Abstract:
Background and Objective:Histone deacetylase(HDAC) inhibitors can inhibit cell signal network function through decreasing expression of multiple genes and proteins,thus affect cell proliferation,survival and chemosensitivity.HDAC inhibitors combined with paclitaxel may enhance the inhibitory effect of drugs on lung cancer cells.This study was to observe the synergistic anti-proliferative effect of HDAC inhibitor trichostatin A (TSA)combined with paclitaxel on lung cancer cell lines H322 and H1299.and to investigate its mechanism. Methods:H322 and H1299 cells were divided into control group,paclitaxel(TAX) group,TSA group, and combination group(TF group,TSA followed by paclitaxel).Cell proliferation was determined by MTT assay.Cell cycle and apoptosis were determined by flow cytometry.The protein expression levels of survivin, ERK,and PARP were determined by Western blot analysis. Results: When combined with TSA,the 50%inhibition concentration(IC_(50))of paclitaxel decreased from (48.07 4±26.12) nmol/L to (6.34±5.72) nmol/L in H322 cells and from (110.64±38.7)nmol/L to(63.7±11.8)nmol/L in H1299 cells.with significant differences(P<0.05).Apoptosis rate of H322 cells was higher in the the TF group than in the TAX group(P<0.05).There were more necrosis cells in the TF group of H1299 cell line than in the other groups.pERK was up-regulated in the TAX group of H322 cell line.Expression of Survivin was up-regulated In the TAX group of two cells.Expressions of Survivin and pERK were downregulated in the TSA and TF groups of two cell lines. Cleaved PARP was detected in the TAX and the TF groups of H322 cells. and its expression was significantly higher in the the TF group than in the TAX group.Cleaved PARP was not detected in each group of H1299 cells.Conclusions:TSA combined with paclitaxel has a synergistic cytotoxicity effect on lung cancer cell lines H322 and H1299 when the cells were treated with TSA foIlowed by paclitaxel.The mechanism may be that TSA down-regulates the survivin highexpression induced by paclitaxel,and blocks pERK protein expression.
